APPLICANT'S ABSTRACT: Opioid dependence is an enduring public health problem and the extent of that problem has escalated because of its association with IV drug use and AIDS. Although widely accepted as a problem of urban areas, opioid dependence in rural areas has been less frequently recognized. This is unfortunate because opioid dependence occurs in, and is a public health problem for, rural areas. Moreover, this lack of recognition has often led to limited treatment alternatives for the rural opioid addict. In this application, we propose to continue the first and only outpatient detoxification clinic to provide pharmacotherapies for opioid dependence in the State of Vermont. Approximately 84 patients per year will participate in clinical pharmacology studies and/or a detoxification study examining buprenorphine, a promising new pharmacotherapy for opioid dependence. These studies will address aspects of buprenorphine's unique clinical pharmacology that will directly impact the manner in which buprenorphine is provided to patients. Specifically, we propose to answer six questions across three series of studies. In the first series, we will continue our research on alternative dosing schedules which has demonstrated that subjects can safely receive buprenorphine every other day or every three days by doubling or tripling the buprenorphine dose, respectively. These dosing schedules will eliminate the need for take- home medication for patients requiring days off from the clinic. In continuing this research, we will answer three questions. First, can buprenorphine be administered safely and effectively every four days? Second, what is the duration of buprenorphine's blockade of the effects of morphine-like opioids during 2-day, 3-day and 4-day dosing schedules? And third, do every 3-day and every 4-day dosing schedules function as reinforcers for opioid-dependent outpatients? In the second series, we will characterize the interaction between buprenorphine and opioid antagonists, to determine whether buprenorphine can facilitate the transition to, and be combined with, opioid antagonists. Specifically we will answer two questions. First, what are the range of conditions under which buprenorphine can be co-administered with naloxone or naltrexone without compromising agonist activity or precipitating withdrawal? And second, can buprenorphine and naltrexone be chronically co- administered without adverse effects? In the third series, we will conduct a detoxification study using daily and 3-day dosing schedules to address the extent to which the buprenorphine dosing schedule influences opioid abstinence and treatment retention during detoxification with buprenorphine. We plan to conduct a minimum of 9 clinical pharmacology studies and 1 detoxification study (for a total of 10 studies) in the five-year period. Overall, this research will provide critical knowledge about buprenorphine's clinical pharmacology that will permit buprenorphine to be used with the greatest efficacy and efficiency in clinical settings. Moreover, this project will positively contribute to the public health status of this region by providing the only outpatient pharmacotherapy services for opioid dependence in the State of Vermont.